CMP Program Links

Department Faculty

Dr. Chu is Director of the Ophthalmic Pathology Service in the Division of Neuropathology and Co-Director of the
Pathologist Investigator Residency/Research Training Program. As principal investigator, she directs a basic
research program focused on mitochondrial pathobiology and Parkinson's disease, and is training faculty for the
Pathology and Neuroscience Graduate programs, the MSTP and the PSTP. She is also a member of the McGowan Institute
for Regenerative Medicine and the Mitochondria, Metabolism and Disease Working Group.

Research Interests

2010 Carnegie Science Awards Profile of Dr. Chu's Research

Dr. Chu's research focuses on mechanisms of neurodegeneration and neuroprotection in Parkinson's and related neurodegenerative diseases. A major focus is delineating why adaptive cellular mechanisms fail to protect neurons. Molecular and biochemical studies in cell culture and mouse models are integrated with studies of diseased human brain tissues. Recent focus has shifted from cell death to mechanisms of mitochondrial quality control and neuritic/synaptic dysfunction at potentially reversible stages.

Work in the Chu laboratory indicates that pathogenic mechanisms related to five models of PD converge on dysregulation of mitochondrial kinase signaling and turnover by autophagy, the process by which cells sequester, degrade and recycle organelles. These include 6-OHDA and MPP+, two parkinsonian neurotoxins, and genetic models based on mutations in PTEN-induced kinase 1 (PINK1), a mitochondrial kinase, the leucine-rich repeat kinase 2 (LRRK 2), a membrane associated multidomain kinase, and ATP13A2, a lysosomal transporter by homology. Analysis of Parkinson disease and Lewy body dementia brain tissues reveal similar alterations in the localization and trafficking of phosphorylated kinases and transcription factors, associated with mitochondrial autophagy, in susceptible populations of neurons early in the disease process.

While there has been growing interest in therapeutic manipulation of autophagy, the potential beneficial or detrimental roles of autophagy in neuronal responses to parkinsonian injury remain undefined. Our work has led to the concept of "autophagic stress," in which imbalanced or excessive induction of autophagy contributes to neuronal dysfunction. For example, ERK1/2 activation, as observed in degenerating human PD neurons and in the chronic MPP+ model, may be harmful to neurons because it activates mitophagy and phosphorylates TFAM at S177 to suppress mitochondrial transcription. We found that PINK1 is essential for maintaining well-functioning mitochondrial networks. Moreover, processed PINK1 that is released from healthy mitochondria serves as a signal of mitochondrial health, suppressing autophagy while engaging pathways that activate pro-differentiation pathways in neurons. Using mass spectrometry, we identified a novel phosphorylation site on the autophagy protein LC3, which protects against neurite degeneration caused by MPP+ or mutant LRRK2. We discovered a novel cargo recognition signal for mitophagy in neurons, which involves exposure of cardiolipin to the surface of damaged mitochondria, where it binds LC3. Furthermore, mutant LRRK2 causes excitotoxic calcium dysregulation in dendrites, which triggers mitochondrial loss and autophagic dendritic degeneration. Current efforts are focused on delineating downstream signaling complexes or targets that regulate mitophagy, calcium homeostasis and mitochondrial function.

Educational Initiatives

Dr. Chu is a member of the Graduate Programs of Cellular and Molecular Pathology (CMP)
and Center for Neuroscience (CNUP),
the Medical Scientist Training Program (MSTP) and the Physician Scientist Training Program (PSTP). She is committed to career
development of pre-doctoral, post-doctoral and physician-scientist trainees, developing and directing for 10 years a MSTP
Professional Development course focused on grant writing and peer-review, which is now emulated by other MSTP and graduate
programs nationwide. She is founding co-director for the Pathologist Investigator
Residency/Research Training Program. This "PI-training track" is designed to develop the next generation of physician-scientist
leaders, independently-funded Academic Pathologists pursuing combined research and diagnostic careers.